During growth within the sand fly and within axenic culture, Leishmania promastigotes undergo differentiation from a dividing noninfective stage to a resting infective or metacyclic stage which is uniquely adapted for life in the vertebrate. For some species of Leishmania (L. donovani and L. major) this development is accompanied by a substantial modification of the surface lipophosphoglycan (LPG) which is the major surface glycoconjugate of these cells. The LPG is densely organized into a glycocalix which effectively masks other surface antigens and which is not expressed on intracellular amastigotes. The complete structures of log phase and metacyclic LPGs of both species have now been determined. The developmental modifications include an elongation of the molecule due to a 2-3 fold increase in the number of phosphorylated oligosaccharated units expressed, and a change in the composition of some of these units. In each case the structural polymorphism is expressed as a loss of terminal galactose residues on the LPG. The effect of this developmental change on the binding of promastigotes to midgut epithelial cells was investigated. An average of 8400 log phase promastigotes bound per midgut, while metacyclic binding was negligible. The binding of log promastigotes was completely inhibited by log phase LPG, but not by metacyclic LPG. The specific oligosaccharide units which mediate the binding is now being studied. In related studies, it was found that the presence of anti-LPG antibodies within an infective bloodmeal inhibited the development of transmissible infections within the sand fly midgut. Thus, immunization of reservoir hosts with LPG may form the basis of a transmission blocking vaccine for leishmaniasis.